Laurence S. Magder

Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus

OBJECTIVE The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt

BACKGROUND The population of Egypt has a heavy burden of liver disease, mostly due to chronic infection with hepatitis C virus (HCV). Overall prevalence of antibody to HCV in the general population is around 15-20%. The risk factor for HCV transmission that specifically sets Egypt apart from other countries is a personal history of parenteral antischistosomal therapy (PAT). A review of the Egyptian PAT mass-treatment campaigns, discontinued only in the 1980s, show a very high potential for transmission of blood-borne pathogens. We examine the relative importance of PAT in the spread of HCV in Egypt. METHODS The degree of exposure to PAT by cohort was estimated from 1961-86 Ministry of Health data. A cohort-specific exposure index for PAT was calculated and compared with cohort-specific HCV prevalence rates in four regions. FINDINGS HCV prevalence was calculated for 8499 Egyptians aged 10-50 years. A significant association between seroprevalence of antibodies to HCV and the exposure index (1.31 [95% CI 1.08-1.59]; p=0.007) was identified across four different regions. In all regions cohort-specific HCV prevalence was lowest in children and young adults than in older cohorts. These lower prevalence rates coincided with the gradual and final replacement of PAT with oral antischistosomal drugs at different points in time in the four regions. INTERPRETATION The data suggest that PAT had a major role in the spread of HCV throughout Egypt. This intensive transmission established a large reservoir of chronic HCV infection, responsible for the high prevalence of HCV infection and current high rates of transmission. Egypts mass campaigns of PAT may represent the worlds largest iatrogenic transmission of blood-borne pathogens.

The Guillain–Barré Syndrome and the 1992–1993 and 1993–1994 Influenza Vaccines

BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992-1993 to 74 in 1993-1994, arousing concern about a possible increase in vaccine-associated risk. METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992-1993 and 1993-1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995-1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit-dialing telephone survey. RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients. The relative risk of the Guillain-Barré syndrome associated with vaccination, adjusted for age, sex, and vaccine season, was 1.7 (95 percent confidence interval, 1.0 to 2.8; P=0.04). The adjusted relative risks were 2.0 for the 1992-1993 season (95 percent confidence interval, 1.0 to 4.3) and 1.5 for the 1993-1994 season (95 percent confidence interval, 0.8 to 2.9). In 9 of the 19 vaccine-associated cases, the onset was in the second week after vaccination, all between day 9 and day 12. CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992-1993 to 1993-1994. For the two seasons combined, the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza.

A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States

The prevalence of infection with the genital herpes simplex virus type 2 (HSV-2) has been difficult to ascertain, primarily because of the large percentage of subclinical cases and the limitations in specificity of serologic assays for antibody to HSV-2. To obtain an improved estimate of the distribution of HSV-2 infection in the United States, we used an HSV type-specific antibody assay to test serum samples from 4201 participants in the second National Health and Nutrition Examination Survey. The results in our sample indicate that in the period from 1976 to 1980, 16.4 percent of the U.S. population 15 to 74 years of age (approximately 25 million persons) was infected with HSV-2 (95 percent confidence interval, 14.2 to 18.6 percent). Age and race were the demographic factors associated most strongly with the presence of HSV-2 antibody. The prevalence of the antibody increased from less than 1 percent in the group under 15 years old to 20.2 percent in the group 30 to 44 years old; it increased only slightly thereafter. In the oldest group, 60 to 74 years of age, the prevalence was 19.7 percent in whites and 64.7 percent in blacks. Among blacks of all age groups, but not whites, higher rates were observed in women than in men. The associations were weaker with respect to marital status, income, education, urban residence, and region of the country. After control for age, sex, and race, only the association with marital status remained significant; the rate was increased in persons previously married--i.e., divorced, separated, or widowed. We conclude that the prevalence of HSV-2 infection in the United States is higher than has previously been recognized and that many infections with this sexually transmitted virus may be subclinical.

Damage in systemic lupus erythematosus and its association with corticosteroids.

OBJECTIVE To evaluate the association between corticosteroid use and organ damage in patients with systemic lupus erythematosus (SLE). METHODS The occurrence and date of organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were determined for 539 patients enrolled in the Hopkins Lupus Cohort Study. The risk of damage associated with the cumulative prednisone dose, high-dose prednisone (> or =60 mg/day for > or =2 months), and pulse methylprednisolone (1,000 mg intravenously for 1-3 days) was estimated using Cox proportional hazards regression analyses, controlling for age, race, and sex. Risk estimates for the cumulative prednisone dose were based on a reference dose of 36.5 gm (e.g., 10 mg of prednisone daily for 10 years [or equivalent]). RESULTS The cumulative prednisone dose was significantly associated with the development of osteoporotic fractures (relative risk [RR] 2.5, 95% confidence interval [95% CI] 1.7, 3.7), symptomatic coronary artery disease (RR 1.7, 95% CI 1.1, 2.5), and cataracts (RR 1.9, 95% CI 1.4, 2.5). Each intravenous pulse was associated with a small increase in the risk of osteoporotic fractures (RR 1.3, 95% CI 1.0, 1.8); however, this result failed to reach statistical significance (P = 0.07). Each 2-month exposure to high-dose prednisone was associated with a 1.2-fold increase in the risk of both avascular necrosis (95% CI 1.1, 1.4) and stroke (95% CI 1.0, 1.5). CONCLUSION SLE patients receiving long-term prednisone therapy were at significant risk of morbidity due to permanent organ damage. Additional research is required to determine the relative contributions of SLE disease activity and corticosteroids to the pathogenesis of specific types of organ damage. Furthermore, new steroid-sparing therapies are needed in order to treat disease activity and minimize cumulative and high-dose prednisone exposure.

Predictors of survival in systemic lupus erythematosus.

Abstract: We conducted the current study to determine the impact of demographic factors, household income, clinical manifestations, disease activity, serologic tests, and calendar year on survival among patients with systemic lupus erythematosus (SLE). In a large prospective cohort of patients with SLE, we used the Kaplan-Meier method to estimate survival probabilities of SLE patients over time since diagnosis. We analyzed the predictors of survival in SLE using Cox proportional hazards models. The study included 1378 patients with SLE, with a median follow-up in the cohort of 6.1 years. One hundred eighteen patients died (8.6%). The overall cumulative probability of survival after disease diagnosis at 5, 10, 15, and 20 years was 95%, 91%, 85%, and 78%, respectively. Based on a multivariable model, age at SLE diagnosis ≥50 years old (hazard ratio [HR] = 5.9; p < .001) and male gender (HR = 2.4; p = .004) were associated with poorer survival. Patients with annual family income <

Lupus Atherosclerosis Prevention Study (LAPS)

25,000 had poorer survival (HR = 1.7; p = .040). The presence of hemolytic anemia in the first year after disease diagnosis (p = .016) or during the follow-up period (p = .031) increased the risk of death. A low complement level during the first year after diagnosis was the only serologic marker of poorer survival (p = .013 for low C3 level and p = .053 for low C4 level). Abbreviations: HR = hazard ratio, SLE = systemic lupus crythematosus, SLEDAI = Systemic Lupus Erythematous Disease Activity Index.

Risk factors for in utero and intrapartum transmission of HIV.

Background Cardiovascular disease is one of the major causes of death in systemic lupus erythematosus (SLE). A study was undertaken to investigate whether treatment with statins would reduce subclinical measures of atherosclerosis over a 2-year period. Methods 200 patients with SLE without clinical cardiovascular disease were randomised to receive atorvastatin 40 mg daily or an identical placebo. At baseline and after 2 years of follow-up, helical CT scanning (for coronary artery calcium) and carotid duplex (for intima media thickness/plaque) were performed. Patients were seen for measures of disease activity at 1 month, 3 months and quarterly thereafter. The primary outcome variable was change in coronary artery calcium. Results At baseline, 43% had coronary artery calcium. At 2 years there was no significant difference between the groups in progression of coronary artery calcium, carotid intima media thickness or carotid plaque. There was no significant difference between the groups in disease activity, measures of inflammation or endothelial cell activation. Conclusion This study provides no evidence that atorvastatin reduces subclinical measures of atherosclerosis or disease activity over 2 years in patients with SLE. In fact, it does not appear to reduce biochemical measures of inflammation. The anti-inflammatory effects of statins observed in the general population were not replicated in this SLE clinical trial. Clinicaltrials.gov (NCT 00120887).

Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis

Objective: To identify predictors of in utero and intrapartum HIV-1 transmission in infants born in the Women and Infants Transmission Study between 1990 and 2000. Methods: In utero HIV-1 infection was defined as an infant with the first positive HIV-1 peripheral blood mononuclear cell culture and/or DNA polymerase chain reaction assay at 7 days of age or younger; intrapartum infection was defined as having a negative HIV-1 culture and/or DNA polymerase chain reaction assay at 7 days of age or younger and the first positive assay after 7 days of age. Results: Of 1709 first-born singleton children with defined HIV-1 infection status, 166 (9.7%) were found to be HIV-1 infected; transmission decreased from 18.1% in 1990-1992 to 1.6% in 1999-2000. Presumed in utero infection was observed in 34% of infected children, and presumed intrapartum infection, in 66%. Among infected children, the proportion with in utero infection increased over time from 27% in 1990-1992 to 80% (4 of 5) in 1999-2000 (P = 0.072). Maternal antenatal viral load and antiretroviral therapy were associated with risk of both in utero and intrapartum transmission. Controlling for maternal antenatal viral load and antiretroviral therapy, low birth weight was significantly associated with in utero transmission, while age, antenatal CD4+ cell percentage, year, birth weight, and duration of membrane rupture were associated with intrapartum transmission. Conclusion: Although there have been significant declines in perinatal HIV-1 infection over time, there has been an increase in the proportion of infections transmitted in utero.

Early risk factors for pregnancy loss in lupus

The objective of this study was to identify clinical predictors of response to initial mycophenolate mofetil (MMF) therapy for membranous lupus nephritis (MLN). We observed the clinical outcomes of patients in the Hopkins Lupus Cohort within the first year of initiation of treatment with MMF therapy for newly diagnosed MLN, classified according to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Complete renal remission was defined as proteinuria less than 500 mg/24 hours. Demographic, clinical, treatment and laboratory data were examined for their association with renal remission. Twenty-nine MLN patients treated with MMF were identified. Eleven (38%) patients achieved complete renal remission by 12 months. Of those taking hydroxychloroquine, 7/11 (64%) were in remission within 12 months compared to only 4/18 (22%) of those not on hyroxychloroquine (P 0.036 based on a log-rank test). This association persisted after controlling for the presence of anti-ds-DNA (P 0.026). Our results provide evidence that hydroxychloroquine has a benefit for renal remission when MMF is used as the initial therapy for MLN. Although hydroxychloroquine is frequently stopped in patients with lupus nephritis, this study suggests it should be started or maintained.